The U.S. Environmental Protection Agencys (EPA) Office of Research
and Development solicits grant applications for the development
of novel mechanistic approaches in human health risk assessment.
Risk assessment is an essential tool for setting environmental and
occupational standards aimed at protecting human health. However,
risk assessment is a relatively new discipline and currently available
methods and relevant information on the exposure to, and the toxicity
of, a given agent are frequently inadequate to fully satisfy the
demands for high quality characterizations of risk. Quantitative
risk assessment methods for both cancer and non-cancer endpoints
have been and continue to be developed. However, the underlying
bases and approaches used to assess human health risk tend to differ,
depending on whether the response is a cancer or non-cancer health
effect.

In 1997, the Commission on Risk Assessment and Risk Management
of the National Research Council concluded that the simple dichotomy
between cancer and non-cancer risk assessment is not fully supported
by current scientific evidence (NRC, 1997). They also stated
that one outcome of this dichotomy is expressions of risk that are
not directly comparable and that differ significantly in defining
maximal exposures considered to have negligible risk. In addition,
the National Research Councils report on Science and Judgment in
Risk Assessment (NRC, 1994) noted the importance of a risk
assessment approach that is less fragmented, more consistent in
application of similar concepts, and more holistic than endpoint-specific
guidelines.

It is now believed that some chemically-induced carcinogenic and
non-carcinogenic effects share common biological pathways or precursor
events. Identification of such common steps and their mechanistic
bases could lead to a more consistent approach in risk assessments.
A framework for how such mechanistic or mode of action information
could be used in risk assessments is lacking. The EPA recognizes
the need to develop a consistent, yet flexible set of principles
and guidelines for using and drawing inferences from scientific
information in risk assessment. This requires improved
methods for more effectively using toxicological information from
both animals and humans for predicting risk for both cancer and
non-cancer outcomes.

Regulatory agencies use a variety of methods to estimate the risks
to humans from environmental and occupational exposures to toxic
agents. Many of these methods are based on toxicological data
derived from animal models, particularly rodents, and have limitations
in their ability to predict human risk. Animal bioassay data
are based on late or terminal stages of complex sequences of events
and processes that are determined by both genotype and phenotype
which differ considerably between rodents and humans. Also,
animal bioassays are generally carried out at doses that exceed
relevant human exposures. Based on these and other criticisms,
it is argued that risk estimations based strictly on animal bioassay
data may be unnecessarily high in some cases and, in others, deceptively
low and not protective of human health.

In order to improve the estimation of risks to humans from exposures
to toxic agents, it is important to continually evaluate all
risk assessment methods and practices in light of new scientific
information so that better risk assessment methodologies can be
developed. A pivotal and emerging source of information
that has significant consequences for developing these new methodologies
comes from the fields of molecular and cellular biology. Over
the last decade, these disciplines have increased our understanding
of biological mechanisms, including the basic pathways and processes
that control cell growth, differentiation, and death, and have provided
new insights into how these pathways and processes are subverted
by toxic agents. While it is clear that some pathways and
processes are common to all eukaryotic cells, there are also clear
phenotypic and genotypic differences that cause responses at other
levels of organization to be cell type- and species-specific.
These differences can profoundly affect how animals and humans respond
to the same toxic agent.

SPECIFIC AREAS OF INTEREST

This Request for Applications (RFA) solicits studies that focus
on the development and characterization of new risk assessment methods,
approaches, and practices that take into account current understanding
of the commonalities and differences in the basic mechanisms through
which animals and humans respond to toxic agents. This includes
studies that identify and characterize the key mechanisms, pathways,
and processes that control the effects of toxic environmental chemicals
on cell proliferation, differentiation, and death in both humans
and animal models. Major emphasis should be on defining those
aspects that are the same or different from both qualitative and
quantitative aspects between animals and humans. Studies that correlate
comparisons between human and rodent primary tissue-specific cells
in vitro and the corresponding rodent tissue in vivo and which focus
on agents or metabolites that have previously tested positive in
animal models are encouraged. Successful proposals will demonstrate
an improved understanding of a toxic response and use of that knowledge
in improving human health risk assessments.

EPA is also interested in research on the use of mechanistic information
in risk assessments from the aspect of the types of information
necessary to:

demonstrate that a substance acts via a particular mode or
mechanism,

demonstrate that two toxic manifestations caused by the same
substance are produced by different modes of action, and

justify the approach for dose-response assessment for chemicals
that produce multiple toxic manifestations, but through similar
or different mode(s) of action.

The purpose of this research is eventually to allow the derivation
of a commonly accepted set of principles defining how mechanistic
or mode of action information can be used in risk assessments, particularly
as it relates to extrapolation issues across and within species, across
time, and from high-to-low doses. Information derived from these
studies will help establish commonalities in the rationale for interspecies
default methods for cancer and non-cancer endpoints. It will also
be important to determine how differing exposure durations and subsequent
toxicity processes may indicate that different measures of dose for
a particular toxic agent, such as peak concentrations of a particular
metabolite, may be more appropriate than the integrated value of the
concentration of an unmetabolized parent compound. Therefore,
comparative studies of chemicals having different metabolic routes
and the conditions influencing those different routes, such as species,
gender, and physiological status, will have a high priority.
The EPA is particularly interested in proposals that address the following
areas:

1. Differences and commonalities between rodents
and humans in the pathways, processes, and mechanisms that control
the effects of toxic chemicals in the environment on cell proliferation
including cell senescence and programmed cell death, cell cycle
control mechanisms, aspects of telomere/telomerase function, and
mechanisms of apoptosis;

2. Differences and commonalities in homologous gene function,
expression, and genomic organization between rodents and humans
that affect the pathways, processes, and mechanisms associated
with the effects of toxic chemicals in the environment;

3. Biological markers (biomarkers) that provide direct
human dose-response data that will reduce the assumptions and
uncertainties that arise from interspecies and high-dose to low-dose
extrapolations, thereby making health risk assessments more reliable,
meaningful, realistic, and cost effective;

4. Studies to determine if mode of action information can
be used in a more consistent way to improve dose-response assessment
across types of adverse health effects. This is true for
both chemicals producing different toxicities by a similar mode
of action and chemicals that produce multiple toxicities by different
modes of action; and

5. Case studies that assess the human health endpoints
by evaluating currently available information on cellular and
molecular mechanisms and modes of action, including studies that
attempt to integrate cancer and non-cancer risk assessment via
statistical or computational techniques. These case studies
should demonstrate the relevance and application of the proposed
approaches to improving human health risk

References:

National Research Council (NRC). 1997. Building a Foundation
for Sound Environmental Decisions, Washington D.C., National
Academy Press.

National Research Council (NRC). 1994. Science and Judgement
in Risk Assessment, Washington D.C., National Academy Press.

FUNDS AVAILABLE

Subject to the availability of funds, up to $6 million is expected
to be awarded in fiscal year 2002 in this program area. The
projected award range is $200,000 to $300,000 per year total costs
for up to 3 years.

ELIGIBILITY

Academic and not-for-profit institutions located in the U.S., and
state or local governments, are eligible under all existing authorizations.
Profit-making firms are not eligible to receive grants from EPA
under this program. Federal agencies and national laboratories
funded by federal agencies (Federally-funded Research and Development
Centers, FFRDCs) may not apply.

Federal employees are not eligible to serve in a principal leadership
role on a grant. FFRDC employees may cooperate or collaborate
with eligible applicants within the limits imposed by applicable
legislation and regulations. They may participate in planning,
conducting, and analyzing the research directed by the principal
investigator, but may not direct projects on behalf of the applicant
organization or principal investigator. The principal investigator's
institution may provide funds through its grant from EPA to a FFRDC
for research personnel, supplies, equipment, and other expenses
directly related to the research. However, salaries for permanent
FFRDC employees may not be provided through this mechanism.

Federal employees may not receive salaries or in other ways augment
their agency's appropriations through grants made by this program.
However, federal employees may interact with grantees so long as
their involvement is not essential to achieving the basic goals
of the grant.1 The principal investigators institution may
also enter into an agreement with a federal agency to purchase or
utilize unique supplies or services unavailable in the private sector.
Examples are purchase of satellite data, census data tapes, chemical
reference standards, analyses, or use of instrumentation or other
facilities not available elsewhere, etc. A written justification
for federal involvement must be included in the application, along
with an assurance from the federal agency involved which commits
it to supply the specified service.

1EPA encourages interaction between its
own laboratory scientists and grant principal investigators for
the purpose of exchanging information in research areas of common
interest that may add value to their respective research activities.
However, this interaction must be incidental to achieving the goals
of the research under a grant. Interaction that is incidental
is not reflected in a research proposal and involves no resource
commitments.

Potential applicants who are uncertain of their eligibility should
contact Jack Puzak in NCER, phone (202) 564-6825, E-mail:
puzak.jack@epa.gov.

STANDARD
INSTRUCTIONS FOR SUBMITTING AN APPLICATION

A set of special instructions on how applicants should apply for
an NCER grant is found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/,
Standard Instructions for Submitting a STAR Application. The
necessary forms for submitting an application will be found on this
web site. Sorting Codes

The need for a sorting code to be used in the application and for
mailing is described in the Standard Instructions for Submitting
a STAR Application. The sorting code for applications submitted
in response to this solicitation is 2001-STAR-T1. The
deadline for receipt of the application by NCER
is no later than 4:00 p.m. ET, September 12, 2001.
DEADLINE EXTENDED TO SEPTEMBER 19, 2001.

CONTACTS

Further information, if needed, may be obtained from one of the
EPA officials indicated below.
E-mail inquiries are preferred.